Cancer is a leading cause of mortality and morbidity. Approaches to treating cancer include surgical intervention to remove tumors and chemotherapy. These approaches can successfully cure some patients. However, even patients that appear to have been cured often suffer a recurrence of the cancer necessitating further therapy. Chemotherapeutic agents generally are nonselective agents that are toxic to cells, such as proliferating cells. Accordingly, such agents may effectively kill cancer cells but also kill healthy cells producing several deleterious side effects.
Certain cancer cells express or overexpress certain cellular components such as cell surface proteins, or express different cellular components when compared to normal cells. One approach to address the short comings of chemotherapeutic approaches to cancer therapy and diagnosis involves targeting cancer cells, for example using antibodies or antibody fragments that bind to proteins that are expressed or overexpressed on cancerous cells. A number of such target proteins have been identified.
Among such proteins scramblase is a protein responsible for the translocation of phospholipids between the two monolayers of a lipid bilayer of a cell membrane. In humans, phospholipid scramblases (PLSCRs) constitute a family of five homologous proteins that are named as hPLSCR1-hPLSCR4. Scramblases are members of the general family of transmembrane lipid transporters known as flippases. The most studied member of this family, phospholipid scramblase 1 (PLSCR1; UniProt accession No. O15162) (a 37 kDa protein), is involved in rapid Ca2+ dependent transbilayer redistribution of plasma membrane phospholipids. Recently the function of PLSCR1 as a phospholipids translocator has been challenged and evidences suggest that PLSCR1 acts as signaling molecule. It has been shown to be involved in protein phosphorylation and as a potential activator of genes in response to interferon and other cytokines (Santosh K S et al, Archives of Biochemistry and Biophysics 462:103-114, 2007). High-level expression of PLSCR1 when stimulated with IFNs in response to viral infection shows its involvement in cellular immunoresponses. Furthermore, its localization to nucleus with increased synthesis in response to IFNs and binding to promoter of IP3R1 gene to induce its expression show that PLSCR1 plays an essential role in cell differentiation.
In a tissue microarray analysis of PLSCR1 expression in multiple tumor tissues and a few normal tissues (see, FIGS. 7(A)˜(D)), it is found that PLSCR1 is highly expressed in many tumor tissues, such as pancreas adenocarcinoma, thyroid medullary carcinoma, esophagus squamous cell carcinoma, esophagus adenocarcinoma, colon adenocarcinoma, rectum adenocarcinoma, uterine cervix squamous cell carcinoma, bladder transitional cell carcinoma; and in normal liver and adrenal gland tissue tissues. Thus, PLSCR1-inhibitors (for example, antibodies, antagonists and siRNA), are developed in the invention and investigated the potential for the treatment of cancers.